EP0074130B1 - New imidazole compounds, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents

New imidazole compounds, process for the preparation thereof and pharmaceutical compositions containing them Download PDF

Info

Publication number
EP0074130B1
EP0074130B1 EP82200960A EP82200960A EP0074130B1 EP 0074130 B1 EP0074130 B1 EP 0074130B1 EP 82200960 A EP82200960 A EP 82200960A EP 82200960 A EP82200960 A EP 82200960A EP 0074130 B1 EP0074130 B1 EP 0074130B1
Authority
EP
European Patent Office
Prior art keywords
imidazole
chlorophenyl
methyl
phenyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP82200960A
Other languages
German (de)
French (fr)
Other versions
EP0074130A2 (en
EP0074130A3 (en
Inventor
Angelo Carenzi
Dario Chiarino
Davide Della Bella
Viviana Frigeni
Carlo Veneziani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zambon SpA
Original Assignee
Zambon SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zambon SpA filed Critical Zambon SpA
Priority to AT82200960T priority Critical patent/ATE56707T1/en
Publication of EP0074130A2 publication Critical patent/EP0074130A2/en
Publication of EP0074130A3 publication Critical patent/EP0074130A3/en
Application granted granted Critical
Publication of EP0074130B1 publication Critical patent/EP0074130B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to new imidazole compounds endowed with analgesic, antipyretic, antiinflammatory activity, to the pharmaceutically acceptable salts thereof, to the pharmaceutical compositions containing them and to some intermediates useful for the preparation of the new imidazole compounds.
  • this invention relates to a compound of formula wherein
  • this invention relates to a compound selected from the group (hereinafter referred to as "GROUP A”) comprising
  • the compounds of this invention may be prepared from the corresponding alcohols of the formula (wherein R 2 , R 3 and R 4 have the meanings disclosed in connection with the products of formula (1) and "GROUP A").
  • the process according to this invention comprises essentially the reaction of a product of the formula (II) or of a reactive derivative thereof with a product of the formula HO-R L , where R 1 has the meanings disclosed in connection with the products of formula (I) and "GROUP A” or with a reactive derivative thereof, to afford a product of this invention or an acid addition salt thereof and, optionally, the treatment of the thus obtained salt with a base to give a product of formula (I) or "GROUP A” which may be then treated with a pharmaceutically acceptable acid to afford a pharmaceutically acceptable acid addition salt thereof.
  • the alcohols of the formula (II) may be prepared by reducing the compounds of the formula wherein R' is hydrogen or alkyl and R 2 , R 3 and R 4 have the meanings disclosed in connection with the products of formula (I) and "GROUP A".
  • the alcohols of the formula (II) wherein R 4 is an aryl radical are also obtained by treating a 2,4-phenylimidazole with formaldehyde or a precursor thereof in the presence of a basic compound such as sodium and potassium hydroxyde and of a suitable solvent such as an aliphatic alcohol, preferably at the boiling temperature of the reaction mixture.
  • the compounds of the formula (III) wherein R 4 is hydrogen may be obtained by condensing the compounds of the formula wherein X is halogen, R 2 and R 3 have the meanings disclosed in connection with the products of formula (I) and "GROUP A” and R' is alkyl, with formamide, in the presence of formic acid, at a temperature comprised between 130 and 160°C.
  • the preparation of the products of this invention may be performed by treating an alcohol (II) with a suitable halogenating agent, such as a hydrogen halide, thionyl chloride or thionyl bromide to give the compounds of the formula wherein X is halogen and R 2 , R 3 and R 4 have the meanings disclosed in connection with the products of formula (I) and "GROUP A".
  • a suitable halogenating agent such as a hydrogen halide, thionyl chloride or thionyl bromide
  • the halogenation is preferably performed at the boiling temperature of the reaction mixture and in the presence of an excess of the halogenating agent.
  • a compound of formula (V) may be reacted under reflux with an excess of a compound R,OH.
  • the ethers of the formula (1) may be also prepared by reacting an alcohol of the formula (II) with a compound of formula R,OH, in the presence of a suitable condensing agent such as p-toluenesulfonic acid.
  • the reduction of the compounds (III) to alcohols (II) may be carried out with a suitable reducing agent, such as lithium aluminum hydride, sodium borohydride, lithium borohydride.
  • a suitable reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride.
  • This step is preferably carried out in the presence of an inert solvent such as tetrahydrofurane, benzene, toluene, dioxane, and at a temperature comprised between 40°C and the boiling temperature of the reaction mixture.
  • a further object of the present invention are the pharmaceutically acceptable salts of the compounds of formula (I) and of "GROUP A” with organic or inorganic acids.
  • organic and inorgaic salts may be mentioned hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, arylsulfonate, maleate, fumarate, citrate, tartrate and benzoate.
  • the antipyretic, analgesic and antiinflammatory activity of the compounds of this invention have been evaluated with several pharmacological tests.
  • ED 50 of Z 1327 and of Z 1356 are respectively 65 and 30 mg/kg/os and 30 and 25 mg/kg/i.p.
  • the analgesic activity has been proved in mice by the test of acetic acid induced stretching inhibition: ED so for Z 1327 is 79 mg/kg/os, whereas ED 50 for Z 1356 is 55 mg/kg/os.
  • ED 50 for Z 1327 is 130 mg/kg/os and 30 mg/kg/i.p.
  • ED 50 for Z 1356 is 100 mg/kg/os and 25 mg/kg/i.p.
  • the compounds have been proved to be very little toxic in mouse; in fact ED 50 of both products after oral administration is higher than 1000 mg/kg, whereas by i.p. route is 400 mg/kg.
  • This invention also relates to pharmaceutical compositions comprising the compounds of the formula (I) and "GROUP A” or the salts thereof as active ingredients.
  • compositions may contain the active ingredient together with an organic or inorganic solid or liquid pharmaceutical excipient suitable for topical, oral, parenteral or rectal administration.
  • compositions may be in solid form such as tablets, dragées, capsules, powders, granular, suppositories, candles, or in liquid form as solutions, suspensions, emulsions, or in semisolid form such as creams, ointments.
  • They may be also prepared in such a way that the release of the drug is prolonged after the administration.
  • They may contain the usual carrier materials and may include auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure, buffers, dyestuffs or flavouring agents.
  • reaction mixture is refluxed for 2.5 hours, then it is cooled to about 0°C and filtered; the precipitate is washed carefully with water until the chloride ion in the aqueous wash is no longer detectable, and then dried at 50 ⁇ 60°C.
  • reaction mixture is heated under reflux for 4.5 hours then is cooled in a water-ice bath and excess hydride is carefully decomposed with 110 ml of water, 110 ml of 15% aqueous NaOH and 330 ml of water.
  • the resulting suspension is filtered and the solid material on the filter is extracted 2-3 times with warm methanol by centrifuging everytime.
  • the methanolic extracts are combined with the preceding tetrahydrofurane filtrate and evaporated.
  • the residue is taken up in water and acetic acid at pH about 4, and heated with a water-bath until the solution is complete.
  • the reaction mixture is then decolourized with activated carbon, filtered and the filtrate is made basic with a concentrated aqueous solution of NH 4 0H.
  • hydrochloride may be prepared (m.p. 190-192°C, crystallized from ethanol).
  • the solution is then decolourized with activated carbon, filtered and dried.
  • the suspension is allowed to cool in a water-ice bath for 1 hour under stirring, then is filtered.
  • a solution of 15 g (0.047 mole) of this compound in 500 ml of anhydrous ethanol is cooled to about 0°C and, a solution of sodium ethylate obtained from 1.1 g (0.0472 mole) of sodium and 50 ml of anhydrous ethanol, is added dropwise under stirring.
  • reaction mixture is heated under reflux for 1.5 hours and then evaporated.
  • residue is dissolved in water made slightly acidic with hydrochloric acid.
  • the combined organic extracts are diluted with ethyl ether, decolourized and evaporated.
  • the resulting solution is cooled and added all at once with 20.1 g (0.1144 mole) of 4-hydroxymethyl-5-phenyl-imidazole and 700 ml of toluene then again is heated to the boiling temperature.
  • the reaction mixture is distilled and stirred for further 4 hours, while toluene is slowly added in order to keep constant the volume of the mixture.
  • the mixture is then distilled for further 1.5 hours without adding toluene and a solid product separates.
  • the suspension is diluted with ether and is shaken with an amount of aqueous solution of sodium hydroxide suitable to neutralize p-toluensulfonic acid.
  • the aqueous layer is discarded, whereas the organic layer is decanted.
  • the solid residue is dissolved in 10% hydrochloric acid.
  • the organic layer is extracted once or twice with 10% hydrochloric acid.
  • the combined aqueous extracts are decolourized with activated carbon and made basic with a diluted aqueous solution of NH 4 0H.
  • the thus obtained precipitate is filtered, washed several times with water, air dried, dissolved in 700 ml of methanol, decolourized with activated carbon and filtered.
  • the evaporation of the methanolic solution affords 16.7 g of a solid product (yield 88.4%).
  • This product is suspended in 50 ml of anhydrous ethanol, neutralized with a suitable amount of saturated ethanolic solution of hydrochlric acid (10-11 ml) and crystallized from ethanol to yield 12.3 g of bis-[(5-phenyl-imidazol-4-yl)-methyl]-ether dihydrochloride which is recrystallized from 96% ethanol to give a pure product, m.p. 215-220°C (dec.).
  • the obtained residue is shaken with ether and with an amount of hydrochloric acid suitable to give a solution.
  • the aqueous layer is separated and washed again with ether, then it is made basic with a concentrated solution of NH 4 0H and cooled.
  • the suspension is extracted several times with ethyl ether; the combined ethereal extracts are washed with water, dried on MgS0 4 , decolourized with activated carbon, filtered and evaporated.
  • the residue is crystallized from 100 ml of a mixture of isopropanol/hexane (24/100 v/v). After cooling to about 0°C, 13.2 g (yield 57.9%) of the free base is obtained; the hydrochloride thereof is prepared by evaporating to dryness the alcoholic solution of the base strongly acidified with an ethanolic solution of hydrochloric acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Epoxy Resins (AREA)
  • Photoreceptors In Electrophotography (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Macromonomer-Based Addition Polymer (AREA)

Abstract

Imidazole compounds of formula (I) <CHEM> their salts and analgesic, antipyretic and antiinflammatory pharmaceutical composition containing them. <??>Intermediates useful in the preparation of said imidazole compounds. <??>Process for preparing the imidazole compounds as well as some intermediates for the preparation thereof.

Description

  • This invention relates to new imidazole compounds endowed with analgesic, antipyretic, antiinflammatory activity, to the pharmaceutically acceptable salts thereof, to the pharmaceutical compositions containing them and to some intermediates useful for the preparation of the new imidazole compounds.
  • More particularly, this invention relates to a compound of formula
    Figure imgb0001
    wherein
    • R, is a straight or branched chain alkyl having from 1 to 10 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms,
    • R2 and R3 are the same or different and each is selected from the group comprising hydrogen, halogen, hydroxy, straight or branched chain alkyl having from 1 to 4 carbon atoms, or alkoxy having from 1 to 4 carbon atoms,
    • R4 is hydrogen, and pharmaceutically acceptable acid addition salts thereof.
  • In addition, this invention relates to a compound selected from the group (hereinafter referred to as "GROUP A") comprising
    • 4-ethoxymethyl-2,5-diphenyl-imidazole,
    • 4-benzyloxymethyl-5-(4-chlorophenyl)-imidazole,
    • 2-phenyl-4-ethoxymethyl-5-(4-chlorophenyl)-imidazole,
    • bis-((5-phenyl-imidazol-4-yl)-methyl]-ether,
    • 4-phenoxymethyl-5-k(4-chlorophenyl)-imidazole,
    • 4-(4-chlorophenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
    • 4-(2-methylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
    • 4-(2,3-dimethylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
    • 4-(4-acetylaminophenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
    • 4-(2-methoxyphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
    • 2-phenyl-4-phenoxymethyl-5-(4-chlorophenyl)-imidazole.
  • Typical instances of compounds of this invention are:
    • 4-ethoxymethyl-5-phenyl-imidazole
    • 4-ethoxymethyl-5-(4-methoxyphenyl)-imidazole
    • 4-ethoxymethyl-5-(4-methylphenyl)-imidazole
    • 4-ethoxymethyl-5-(2-naphthyl)-imidazole
    • 4-ethoxymethyl-5-(3-chlorophenyl)-imidazole
    • 4-ethoxymethyl-5-(2-chlorophenyl)-imidazole
    • 4-ethoxymethyl-5-(2-methoxyphenyl)-imidazole
    • 4-ethoxymethyl-5-(4-methoxythiophenyl)-imidazole
    • 4-ethoxymethyl-5-(4-methylsulfonylphenyl)-imidazole
    • 4-ethoxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-ethoxymethyl-5-(3-methoxyphenyl)-imidazole
    • 4-ethoxymethyl-5-(3,4-dimethoxyphenyl)-imidazole
    • 4-cyclohexyloxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-isopropoxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-ethoxymethyl-2,5-diphenyl-imidazole
    • 4-methoxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-n-butoxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-benzyloxymethyl-5-(4-chlorophenyl)-imidazole
    • 2-phenyl-4-ethoxymethyl-5-(4-chlorophenyl)-imidazole
    • bis-[(5-phenyl-imidazol-4-yl)-methyl]-ether
    • 4-phenoxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-(4-chlorophenoxy)-methyl-5-(4-chlorophenyl)-imidazole
    • 4-(2-methylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole
    • 4-(2,3-dimethylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole
    • 4-(2-methoxyphenoxy)-methyl-5-(4-chlorophenyl)-imidazole
    • 2-phenyl-4-phenoxymethyl-5-(4-chlorophenyl)-imidazole.
  • The compounds of this invention may be prepared from the corresponding alcohols of the formula
    Figure imgb0002
    (wherein R2, R3 and R4 have the meanings disclosed in connection with the products of formula (1) and "GROUP A").
    • Typical instances of the compounds of the general formula (II) are:
    • 4-hydroxymethyl-5-phenyl-imidazole
    • 4-hydroxymethyl-5-(4-methylphenyl)-imidazole
    • 4-hydroxymethyl-5-(2-naphthyl)-imidazole
    • 4-hydroxymethyl-5-(3-chlorophenyl)-imidazole
    • 4-hydroxymethyl-5-(2-chlorophenyl)-imidazole
    • 4-hydroxymethyl-5-(2-methoxyphenyl)-imidazole
    • 4-hydroxymethyl-5-(4-methylthiophenyl)-imidazole
    • 4-hydroxymethyl-5-(4-methylsulfonylphenyl)-imidazole
    • 4-hydroxymethyl-5-(4-chlorophenyl)-imidazole
    • 4-hydroxymethyl-5-(3,4-dimethoxyphenyl)-imidazole
    • 4-hydroxymethyl-5-(3-methoxyphenyl-imidazole
    • 2,5-diphenyl-4-hydroxymethyl-imidazole.
  • The process according to this invention comprises essentially the reaction of a product of the formula (II) or of a reactive derivative thereof with a product of the formula HO-RL, where R1 has the meanings disclosed in connection with the products of formula (I) and "GROUP A" or with a reactive derivative thereof, to afford a product of this invention or an acid addition salt thereof and, optionally, the treatment of the thus obtained salt with a base to give a product of formula (I) or "GROUP A" which may be then treated with a pharmaceutically acceptable acid to afford a pharmaceutically acceptable acid addition salt thereof. The alcohols of the formula (II) may be prepared by reducing the compounds of the formula
    Figure imgb0003
    wherein R' is hydrogen or alkyl and R2, R3 and R4 have the meanings disclosed in connection with the products of formula (I) and "GROUP A".
    • Typical instances of the compounds of the general formula (III) are:
    • 4-carbethoxy-5-phenyl-imidazole
    • 4-carbethoxy-5-(4-methylphenyl)-imidazole
    • 4-carbethoxy-5-(4-chlorophenyl)-imidazole
    • 4-carbethoxy-5-(2-naphthyl)-imidazole
    • 4-carbethoxy-5-(3-chlorophenyl)-imidazole
    • 4-carbethoxy-5-(2-chlorophenyl)-imidazole
    • 4-carbethoxy-5-(2-methoxyphenyl)-imidazole
    • 4-carbethoxy-5-(4-methoxyphenyl)-imidazole
    • 4-carbethoxy-5-(3,4-dimethoxyphenyl)-imidazole
    • 4-carbethoxy-5-(3-methoxyphenyl)-imidazole
    • 4-carbethoxy-5-(4-methylthiophenyl)-imidazole
    • 4-carbethoxy-5-(4-methylsulfonyl-phenyl)-imidazole.
  • Alternatively the alcohols of the formula (II) wherein R4 is an aryl radical are also obtained by treating a 2,4-phenylimidazole with formaldehyde or a precursor thereof in the presence of a basic compound such as sodium and potassium hydroxyde and of a suitable solvent such as an aliphatic alcohol, preferably at the boiling temperature of the reaction mixture.
  • Finally, the compounds of the formula (III) wherein R4 is hydrogen may be obtained by condensing the compounds of the formula
    Figure imgb0004
    wherein X is halogen, R2 and R3 have the meanings disclosed in connection with the products of formula (I) and "GROUP A" and R' is alkyl, with formamide, in the presence of formic acid, at a temperature comprised between 130 and 160°C.
  • The preparation of the products of this invention may be performed by treating an alcohol (II) with a suitable halogenating agent, such as a hydrogen halide, thionyl chloride or thionyl bromide to give the compounds of the formula
    Figure imgb0005
    wherein X is halogen and R2, R3 and R4 have the meanings disclosed in connection with the products of formula (I) and "GROUP A".
  • The halogenation is preferably performed at the boiling temperature of the reaction mixture and in the presence of an excess of the halogenating agent.
  • The thus obtained compounds (V) are then reacted with a compound of the formula R,OH or R,OM (wherein R1 has the meanings disclosed in connection with the products of formula (I) and "GROUP A" and M is a metal, preferably sodium) to afford the corresponding ethers. When it is used a compound of formula R,OM the reaction is carried out in the presence of a suitable solvent and at a temperature comprised between -15° and the boiling temperature of the reaction mixture. For each mole of compound (V) are added from 1 to 2 moles of compound R,OM.
  • Alternatively, a compound of formula (V) may be reacted under reflux with an excess of a compound R,OH.
  • The ethers of the formula (1) may be also prepared by reacting an alcohol of the formula (II) with a compound of formula R,OH, in the presence of a suitable condensing agent such as p-toluenesulfonic acid.
  • The reduction of the compounds (III) to alcohols (II) may be carried out with a suitable reducing agent, such as lithium aluminum hydride, sodium borohydride, lithium borohydride. This step is preferably carried out in the presence of an inert solvent such as tetrahydrofurane, benzene, toluene, dioxane, and at a temperature comprised between 40°C and the boiling temperature of the reaction mixture.
  • A further object of the present invention are the pharmaceutically acceptable salts of the compounds of formula (I) and of "GROUP A" with organic or inorganic acids.
  • Among the organic and inorgaic salts may be mentioned hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, arylsulfonate, maleate, fumarate, citrate, tartrate and benzoate.
  • The antipyretic, analgesic and antiinflammatory activity of the compounds of this invention have been evaluated with several pharmacological tests.
  • The data reported below have been obtained by testing 4-ethoxymethyl-5-(4-chlorophenyl)-imidazole and 4-phenoxymethyl-5-(4-chlorophenyl)-imidazole (which will be indicated hereibelow for brevity as Z 1327 and Z 1356 respectively) and are illustrative of the pharmacological profile of all the compounds of the formula (I).
  • The antipyretic activity has been proved in rats by means of the test of the yeast induced hyperthermy inhibition: ED50of Z 1327 and of Z 1356 are respectively 65 and 30 mg/kg/os and 30 and 25 mg/kg/i.p.
  • The analgesic activity has been proved in mice by the test of acetic acid induced stretching inhibition: EDso for Z 1327 is 79 mg/kg/os, whereas ED50 for Z 1356 is 55 mg/kg/os.
  • Finally, the antiinflammatory activity has been proved in rats by the carrageenin oedema test: ED50 for Z 1327 is 130 mg/kg/os and 30 mg/kg/i.p., whereas ED50 for Z 1356 is 100 mg/kg/os and 25 mg/kg/i.p.
  • Furthermore, the compounds have been proved to be very little toxic in mouse; in fact ED50 of both products after oral administration is higher than 1000 mg/kg, whereas by i.p. route is 400 mg/kg.
  • This invention also relates to pharmaceutical compositions comprising the compounds of the formula (I) and "GROUP A" or the salts thereof as active ingredients.
  • The compositions may contain the active ingredient together with an organic or inorganic solid or liquid pharmaceutical excipient suitable for topical, oral, parenteral or rectal administration.
  • The pharmaceutical compositions may be in solid form such as tablets, dragées, capsules, powders, granular, suppositories, candles, or in liquid form as solutions, suspensions, emulsions, or in semisolid form such as creams, ointments.
  • They may be also prepared in such a way that the release of the drug is prolonged after the administration.
  • They may contain the usual carrier materials and may include auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure, buffers, dyestuffs or flavouring agents.
  • They are prepared according to known methods and may further contain other valuable substances.
  • All the products described in the examples have been characterized by NMR.
  • It is not always necessary to isolate and to purify, as described in the following examples, the intermediates; the most part of them, in fact, may be used in the subsequent steps of the process without any previous separation or purification.
  • The following examples are given to illustrate the present invention without limiting it in any way.
    • Example 1 4-carbethoxy-5-phenyl-imidazole
  • 22.7 g (0.1 mole) of ethyl 2-chloro-3-oxo-3-phenyl propanoate is added dropwise fairly rapidly into a vigorously stirred solution of 2.3 g (0.049 mole) of formic acid and of 7.5 ml of water in 39.8 ml (0.883 mole) of formamide heated at 135-140°C.
  • When the addition is complete the reaction mixture is refluxed for 2.5 hours, then it is cooled to about 0°C and filtered; the precipitate is washed carefully with water until the chloride ion in the aqueous wash is no longer detectable, and then dried at 50―60°C.
  • 11.7 g (yield 54.1 %) of crude product is obtained which is crystallized twice from 96% ethanol to give 8.4 g of pure 4-carbethoxy-5-phenyl-imidazole (yield 38.8%), m.p. 22&-228°C. In a similar manner the following compounds have been prepared:
    • 4-carbethoxy-5-(4-methoxyphenyl)-imidazole, m.p. 203-205°C
    • 4-carbethoxy-5-(3,4-dimethoxyphenyl)-imidazole, m.p. 181-183°C
    • 4-carbethoxy-5-(3-methoxyphenyl)-imidazole, m.p. 146-1510C
    • 4-carbethoxy-5-(4-methylthiophenyl)-imidazole, m.p. 192-194°C;
      from this product, by the usual oxidation techniques, the 4-carbethoxy-5-(4-methylsulfonyl-phenyl)-imidazole is obtained, m.p. 211-213°C.
    Example 2 4-hydroxymethyl-5-phenyl-imidazole hydrochloride
  • 293.5 g (1.357 mole) of 4-carbethoxy-5-phenyl-imidazole is added portionwise to a suspension of 103 g (2.714 mole) of LiAIH4 in 4500 ml of tetrahydrofurane cooled in a water-bath.
  • The reaction mixture is heated under reflux for 4.5 hours then is cooled in a water-ice bath and excess hydride is carefully decomposed with 110 ml of water, 110 ml of 15% aqueous NaOH and 330 ml of water.
  • The resulting suspension is filtered and the solid material on the filter is extracted 2-3 times with warm methanol by centrifuging everytime. The methanolic extracts are combined with the preceding tetrahydrofurane filtrate and evaporated.
  • The residue is taken up in water and acetic acid at pH about 4, and heated with a water-bath until the solution is complete. The reaction mixture is then decolourized with activated carbon, filtered and the filtrate is made basic with a concentrated aqueous solution of NH40H.
  • The resulting mixture is cooled, filtered and the precipitate is washed thoroughly with water and dried to yield 213 g (90.2%) of 4-hydroxymethyl-5-phenyl-imidazole, m.p. 174-175°C (dec.).
  • From the thus obtained compound and according to the usual techniques the hydrochloride may be prepared (m.p. 190-192°C, crystallized from ethanol).
  • In a similar manner the following compounds may be prepared:
    • 4-hydroxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride; m.p. 165-168°C (dec.)
    • 4-hydroxymethyl-5-(3,4-dimethoxyphenyl)-imidazole hydrochloride; m.p. 197°C (dec.)
    • 4-hydroxymethyl-5-(3-methoxyphenyl)-imidazole hydrochloride; m.p. 130-134°C.
    Example 3 2,5-diphenyl-4-hydroxymethyl-imidazole hydrochloride
  • 5 g (0.0227 mole) of 2,4-diphenyi-imidazoie, 0.85 g (0.0283 mole) of paraformaldehyde and 0.1 g of finely ground potassium hydroxide are dissolved in 29 ml of warm methanol and heated under reflux for 90 hours.
  • The solution is then decolourized with activated carbon, filtered and dried.
  • Water and chloroform are added to the residue by stirring; the insoluble solid of both the layers is filtered, washed with water and chloroform and dried. 2.8 g (yield 49.3%) of crude product is thus obtained, which is crystallized from methanol to afford 1.1 g of 2,5-diphenyl-4-hydroxymethyl-imidazole, m.p. 20&-207°C (dec.) By the usual techniques the hydrochloride has been obtained, m.p. about 220°C (dec.).
    • Example 4 4-ethoxymethyl-5-phenyl-imidazole hydrochloride
  • 30 g (0.172 mole) of 4-hydroxymethyl-5-phenyl-imidazole is dissolved in 79 ml of 47% aqueous hydrobromic acid; the solution is stirred vigorously and heated under reflux for 5 hours.
  • The suspension is allowed to cool in a water-ice bath for 1 hour under stirring, then is filtered.
  • The precipitate is washed with acetone and ethyl ether and dried under vacuum at room temperature. 48 g (yield 87.6%) of 4-bromo-methyl-5-phenyl-imidazole hydrobromide is obtained.
  • A solution of 15 g (0.047 mole) of this compound in 500 ml of anhydrous ethanol is cooled to about 0°C and, a solution of sodium ethylate obtained from 1.1 g (0.0472 mole) of sodium and 50 ml of anhydrous ethanol, is added dropwise under stirring.
  • The reaction mixture is heated under reflux for 1.5 hours and then evaporated. The residue is dissolved in water made slightly acidic with hydrochloric acid.
  • After the solution is decolourized with carbon and made basic with a concentrated aqueous solution of NH40H, it is extracted several times with ethyl ether, then one with ethyl acetate and then finally once with chloroform.
  • The combined organic extracts are diluted with ethyl ether, decolourized and evaporated.
  • 100 ml of pentane is added to the residue and the mixture is heated to the boiling temperature. The solid is filtered and dried under vacuum at 50°C to give 6 g (yield 62.9%) of the title compound which is dissolved in 25 ml of anhydrous ethanol and acidified with a saturated ethanolic solution of hydrochloric acid.
  • The solution is allowed to stand at about 0°C a long time, and provides a precipitate which is filtered, washed with acetone and dried under vacuum at 60°C to give 4.2 g (yield 37.3%) of 4-ethoxymethyl-5-phenyl-imidazole hydrochloride; m.p. 176-178°C (dec.).
    • Example 5 4-ethoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride
  • 12.25 g (0.05 mole) of 4-hydroxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride is added to stirred thionyl chloride (30 ml). The solution is heated to the boiling temperature and stirred for further 2 hours. After cooling to about 0°C for about 30 min. the reaction mixture is filtered; the solid on the filter is washed with ethyl ether and dried under vacuum to give 12.7 g (yield 96.6%) of 4-chloromethyl-5-(4-chlorophenyl)-imidazole hydrochloride.
  • 65 g (0.247 mole) of this product is dissolved in 780 ml of anhydrous ethanol, the thus obtained solution is heated under reflux and stirred for 24 hours, then is evaporated to dryness to provide 66.3 g of a residue which is crystallized from isopropanol.
  • 58.9 g of pure product is obtained, m.p. 175-177°C (dec.); yield 87.4%.
    • In a manner similar to that described in examples 4 or 5 the following compounds have been prepared
    • 4-ethoxymethyl-5-(3-methoxyphenyl)-imidazole hydrochloride, m.p. 148-149°C
    • 4-ethoxymethyl-5-(3,4-dimethoxyphenyl)-imidazole hydrochloride, m.p. 180-182°C
    • 4-cyclohexyloxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 178-180°C
    • 4-isopropoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 160-161°C (dec.)
    • 4-ethoxymethyi-2,5-diphenyi-imidazoie hydrochloride, m.p. 168-170°C (dec.)
    • 4-methoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 181-183°C (dec.)
    • 4-n-butoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 158-160°C
    • 4-benzyloxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 159-161°C
    • 2-phenyl-4-ethoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 260°C.
    Example 6 Bis-[(5-phenyl-imdiazol-4-yl)-methyl]-ether dihydrochloride
  • 26 g (0.1468 mole) of p-toluensulfonic acid monohydrate in 1500 ml of toluene is anhydrified by distillation.
  • The resulting solution is cooled and added all at once with 20.1 g (0.1144 mole) of 4-hydroxymethyl-5-phenyl-imidazole and 700 ml of toluene then again is heated to the boiling temperature. The reaction mixture is distilled and stirred for further 4 hours, while toluene is slowly added in order to keep constant the volume of the mixture. The mixture is then distilled for further 1.5 hours without adding toluene and a solid product separates. The suspension is diluted with ether and is shaken with an amount of aqueous solution of sodium hydroxide suitable to neutralize p-toluensulfonic acid.
  • The aqueous layer is discarded, whereas the organic layer is decanted. The solid residue is dissolved in 10% hydrochloric acid. The organic layer is extracted once or twice with 10% hydrochloric acid.
  • The combined aqueous extracts are decolourized with activated carbon and made basic with a diluted aqueous solution of NH40H. The thus obtained precipitate is filtered, washed several times with water, air dried, dissolved in 700 ml of methanol, decolourized with activated carbon and filtered. The evaporation of the methanolic solution affords 16.7 g of a solid product (yield 88.4%).
  • This product is suspended in 50 ml of anhydrous ethanol, neutralized with a suitable amount of saturated ethanolic solution of hydrochlric acid (10-11 ml) and crystallized from ethanol to yield 12.3 g of bis-[(5-phenyl-imidazol-4-yl)-methyl]-ether dihydrochloride which is recrystallized from 96% ethanol to give a pure product, m.p. 215-220°C (dec.).
    • Example 7 4-phenoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride
  • A solution of 15.2 g (0.16 mole) of phenol in 50 ml of ethanol is added to a solution of sodium ethylate in ethanol prepared from 3.7 g (0.16 mole) of sodium and 300 ml of ethanol. The reaction mixture is stirred at room temperature for 2.5 hours, then is cooled to -18°C/-15°C.
  • A solution of 21.1 g (0.08 mole) of 4-chloromethyl-5-(4-chlorophenyl)-imidazole hydrochloride in 500 ml of ethanol is added dropwise under stirring and while the temperature is maintained at about -10°C. The reaction mixture is allowed to stand at room temperature overnight, then is filtered and the filtrate is evaporated under reduced pressure.
  • The obtained residue is shaken with ether and with an amount of hydrochloric acid suitable to give a solution. The aqueous layer is separated and washed again with ether, then it is made basic with a concentrated solution of NH40H and cooled.
  • The suspension is extracted several times with ethyl ether; the combined ethereal extracts are washed with water, dried on MgS04, decolourized with activated carbon, filtered and evaporated.
  • The residue is crystallized from 100 ml of a mixture of isopropanol/hexane (24/100 v/v). After cooling to about 0°C, 13.2 g (yield 57.9%) of the free base is obtained; the hydrochloride thereof is prepared by evaporating to dryness the alcoholic solution of the base strongly acidified with an ethanolic solution of hydrochloric acid.
  • Two crystallizations from water give 10.4 g (yield 40.5%) of 4-phenoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 167-168°C.
    • In a similar manner the following compounds have been prepared
    • 4-(4-chlorophenoxy)-methyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 188-190°C
    • 4-(2-methylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 166-168°C
    • 4-(2,3-dimethylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 182-184°C
    • 4-(4-acetylaminophenoxy)-methyl-5-(4-chlorophenyl)-imidazole, m.p. 176-178°C
    • 4-(2-methoxyphenoxy)-methyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 164―167°C
    • 2-phenyl-4-phenoxymethyl-5-(4-chlorophenyl)-imidazole hydrochloride, m.p. 210-215°C (dec.).

Claims (8)

1. A product of the general formula
Figure imgb0006
wherein
R, is a straight or branched chain alkyl having from 1 to 10 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms,
R2 and R3 are the same or different and each is selected from the group comprising hydrogen, halogen, hydroxy, straight or branched chain alkyl having from 1 to 4 carbon atoms or alkoxy having from 1 to 4 carbon atoms,
R4 is hydrogen, and pharmaceutically acceptable acid addition salts thereof.
2. A product of the general formula
Figure imgb0007
wherein
R, is selected from the group comprising a straight or branched chain alkyl having from 1 to 10 carbon atoms and pharmaceutically acceptable acid addition salts thereof.
3. 4-ethoxy-methyl-5-(4-chlorophenyl)-imidazole and pharmaceutically acceptable acid addition salts thereof.
4. A compound selected from the group comprising
4-ethoxymethyl-2,5-diphenyl-imidazole,
4-benzyloxymethyl-5-(4-chlorophenyl)-imidazole,
2-phenyl-4-ethoxymethyl-5-(4-chlorophenyl)-imidazole,
bis-[(5-phenyl-imidazol-4-yl)-methyl]-ether,
4-phenoxymethyl-5-(4-chlorophenyl)-imidazole,
4-(4-chlorophenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(2-methylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(2,3-dimethylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(4-acetylaminophenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(2-methoxyphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
2-phenyl-4-phenoxymethyl-5-(4-chlorophenyl)-imidazole and pharmaceutically acceptable acid addition salts thereof.
5. A pharmaceutical composition containing an effective amount of a product of the formula
Figure imgb0008
wherein
R, is a straight or branched chain alkyl having from 1 to 10 carbon atoms or a cycloalkyl having from 3 to 6 carbon atoms,
R2 and R3 are the same or different and each is selected from the group comprising hydrogen, halogen, hydroxy, straight or branched chain alkyl having from 1 to 4 carbon atoms, or alkoxy having from 1 to 4 carbon atoms,
R4 is hydrogen, or of a pharmaceutically acceptable acid addition salt thereof.
6. A pharmaceutical compositions containing an effective amount of a product of the formula
Figure imgb0009
wherein
R, is selected from the group comprising a straight or branched chain alkyl having from 1 to 10 carbon atoms
or of a pharmaceutically acceptable acid addition salt thereof together with pharmaceutically acceptable carriers.
7. A pharmaceutical composition containing an effective amount of 4-ethoxy-methyl-5-(4-chlorophenyl)-imidazole or of a pharmaceutically acceptable acid addition salt thereof together with pharmaceutically acceptable carriers.
8. A pharmaceutical composition containing an effective amount of a compound selected from the group comprising
4-ethoxymethyl-2,5-diphenyl-imidazole,
4-benzyloxymethyl-5-(4-chlorophenyl)-imidazole,
2-phenyl-4-ethoxymethyl-5-(4-chlorophenyl)-imidazole,
bis-[(5-phenyl-imidazol-4-yl)-methyl]-ether,
4-phenoxymethyl-5-(4-chlorophenyl)-imidazole,
4-(4-chlorophenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(2-methylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(2,3-dimethylphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(4-acetylaminophenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
4-(2-methoxyphenoxy)-methyl-5-(4-chlorophenyl)-imidazole,
2-phenyl-4-phenoxymethyl-5-(4-chlorophenyl)-imidazole or of a pharmaceutically acceptable acid addition salt thereof.
EP82200960A 1981-07-31 1982-07-27 New imidazole compounds, process for the preparation thereof and pharmaceutical compositions containing them Expired - Lifetime EP0074130B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT82200960T ATE56707T1 (en) 1981-07-31 1982-07-27 IMIDAZOLE COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND THEIR PHARMACEUTICAL COMPOSITIONS.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2327081 1981-07-31
IT23270/81A IT1168008B (en) 1981-07-31 1981-07-31 IMIDAZOL-ETERI AND ESTER, PROCEDURES TO PREPARE THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Publications (3)

Publication Number Publication Date
EP0074130A2 EP0074130A2 (en) 1983-03-16
EP0074130A3 EP0074130A3 (en) 1983-08-10
EP0074130B1 true EP0074130B1 (en) 1990-09-19

Family

ID=11205498

Family Applications (1)

Application Number Title Priority Date Filing Date
EP82200960A Expired - Lifetime EP0074130B1 (en) 1981-07-31 1982-07-27 New imidazole compounds, process for the preparation thereof and pharmaceutical compositions containing them

Country Status (13)

Country Link
US (1) US4560696A (en)
EP (1) EP0074130B1 (en)
JP (1) JPS5849369A (en)
AT (1) ATE56707T1 (en)
AU (1) AU557494B2 (en)
CA (1) CA1186315A (en)
DE (1) DE3280245D1 (en)
DK (1) DK158944C (en)
ES (1) ES515895A0 (en)
GR (1) GR76886B (en)
IT (1) IT1168008B (en)
PT (1) PT75338B (en)
ZA (1) ZA825428B (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206257A (en) * 1987-03-05 1993-04-27 May & Baker Limited Pesticidal method using 2-phenylimidazole derivatives
EP0609457B1 (en) * 1992-07-20 1997-10-29 Eisai Co., Ltd. Benzene derivative
US6613789B2 (en) 1994-07-28 2003-09-02 G. D. Searle & Co. Heterocyclo-substituted imidazoles for the treatment of inflammation
US5616601A (en) * 1994-07-28 1997-04-01 Gd Searle & Co 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
AR024222A1 (en) * 1998-10-16 2002-09-25 Palau Pharma Sa IMIDAZOLES WITH ANTI-INFLAMMATORY ACTIVITY A PROCEDURE FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
ES2243337T3 (en) 1999-12-16 2005-12-01 Schering Corporation ANTAGONIST REPLACED IMIDAZOLS OF THE Y5 NEUROPEPTIDE Y.
ES2159489B1 (en) * 2000-03-23 2002-04-16 Uriach & Cia Sa J NEW IMIDAZOL DERIVATIVES WITH ANTI-INFLAMMATORY ACTIVITY.
CN102775354A (en) * 2011-05-10 2012-11-14 无锡立诺康医药科技有限公司 Process method for synthesizing 4-aryl-5-carboxylic acid imidazole and ester thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1570212A (en) * 1975-10-29 1980-06-25 Smithkline Corp Imidazoles
US4104473A (en) * 1976-04-23 1978-08-01 Shikoku Chemicals Corporation Novel imidazole compounds and process for preparations thereof
US4124766A (en) * 1977-02-03 1978-11-07 American Cyanamid Company Substituted 3-(4-imidazolylmethylene)carbazic and thiocarbazic acid esters
US4139708A (en) * 1977-05-24 1979-02-13 Sk&F Lab Co. Intermediates and processes useful for preparing medicinal agents imidazolemethylphosphonium salts
KR810000359B1 (en) * 1980-03-31 1981-04-22 한국과학기술원 Preparing process for hydroxy methyl imidazole compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Lehrbuch der Organischen Chemie (1976) Bayer *
Pharmazeutische Chemie, E. Schröder (1982) pages 36-38 *

Also Published As

Publication number Publication date
IT1168008B (en) 1987-05-20
JPH0337549B2 (en) 1991-06-05
ES8403463A1 (en) 1984-04-01
PT75338B (en) 1985-01-04
US4560696A (en) 1985-12-24
DK158944C (en) 1991-01-21
DK158944B (en) 1990-08-06
EP0074130A2 (en) 1983-03-16
CA1186315A (en) 1985-04-30
ES515895A0 (en) 1984-04-01
GR76886B (en) 1984-09-04
DK341882A (en) 1983-02-01
IT8123270A0 (en) 1981-07-31
AU557494B2 (en) 1986-12-24
PT75338A (en) 1982-08-01
DE3280245D1 (en) 1990-10-25
JPS5849369A (en) 1983-03-23
AU8660582A (en) 1983-02-03
ZA825428B (en) 1983-08-31
EP0074130A3 (en) 1983-08-10
ATE56707T1 (en) 1990-10-15

Similar Documents

Publication Publication Date Title
US4355040A (en) Hypotensive imidazole-5-acetic acid derivatives
EP0311447B1 (en) Aromatase inhibiting 4(5)-imidazoles
EP0074130B1 (en) New imidazole compounds, process for the preparation thereof and pharmaceutical compositions containing them
KR830002451B1 (en) Process for preparing imidazolyl vinyl ether
US5296498A (en) Guanidine compounds
JP2633087B2 (en) Novel 1- (arylalkylaminoalkyl) imidazole compounds
US2820817A (en) Oxygenated indan compounds and method of making the same
SU1710558A1 (en) Substituted 1h-imidazoles, showing antiischemic activity
FI75560C (en) FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA 4- (HYDROXIALKYLTIOMETYL) PYRIDINER.
US4347251A (en) Novel 3-substituted amino-1-substituted heteroaryl-2-pyrazolines
SI9200113A (en) New selective aromatase inhibiting 4(5)-imidazoles
US4282230A (en) Imidazolylethoxy derivatives of quinoline-2- or 4-methanols, antimicrobial compositions containing them and method for treating bacterial or fungal infections with them
JPH0645604B2 (en) Imidazole derivative
US6362211B2 (en) Polycyclic indanylimidazoles with alpha2 adrenergic activity
FI61868C (en) PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC EQUIPMENT 2-ENYLBICYKLOOKTAN- OCH OKTENDERIVAT
AU2001258469A1 (en) New polycyclic indanylimidazoles with alpha2 adrenergic activity
US4243665A (en) 2-Heterocyclylalkyl-6-methoxy-naphthalenes
US4778803A (en) Nitrogen-arylmethoxy-thiophene derivatives and acid addition salts thereof, and pharmaceutical preparations containing these compounds
US4085142A (en) 2-Aryl-6-arylidene-1-(substituted aminoalkoxy)-1-cyclohexenes
SE443560B (en) ANALOGY PROCEDURE FOR PREPARATION OF 1-AMINO-LOWER ALKYL-3,4-DIPHENYL-1H-PYRAZOLES
US3879462A (en) Amino substituted tetrahydropleiadenes
US4317831A (en) Antimicrobial derivatives of 3-(1H-imidazol-1-yl)-2-propen-1-ones
JP2523015B2 (en) 1,1,2-triaryl-1-butene derivative
US4097609A (en) 2,4-Disubstituted-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrenes
US3725432A (en) Biphenylyl pyrazole compounds

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17P Request for examination filed

Effective date: 19840210

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

ITF It: translation for a ep patent filed
AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19900919

Ref country code: NL

Effective date: 19900919

Ref country code: AT

Effective date: 19900919

REF Corresponds to:

Ref document number: 56707

Country of ref document: AT

Date of ref document: 19901015

Kind code of ref document: T

REF Corresponds to:

Ref document number: 3280245

Country of ref document: DE

Date of ref document: 19901025

ET Fr: translation filed
NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19910703

Year of fee payment: 10

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

ITTA It: last paid annual fee
26N No opposition filed
EPTA Lu: last paid annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19920727

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19930623

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Effective date: 19940731

BERE Be: lapsed

Owner name: ZAMBON S.P.A.

Effective date: 19940731

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19980625

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19980708

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19980720

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19980930

Year of fee payment: 17

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990727

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990731

Ref country code: FR

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 19990731

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19990731

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19990727

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000503

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST